1. Field of the Invention
This invention relates to optionally substituted 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-N-(1H-tetrazol-5-yl)carboxamide derivatives and to their use as inhibitors of allergic reactions.
2. Description of the Prior Art
Various medicinal agents have been employed in the treatment of allergic reactions such as bronchial asthma and allergic rhinitis which are believed to result mainly from antigen-antibody interaction. With respect to bronchial asthma, one of the most serious of these allergically-mediated diseases, bronchodilators such as theophylline, isoproterenol, epinephrine and atropine are used primarily in providing symptomatic relief. These agents, however, have undesirable side effects, e.g. cardiac stimulation and gastrointestinal distress.
With the recent introduction of disodium cromoglycate described by J. S. G. Cox, et al. in Adv. in Drug Res., 5, 115-196 (1970), the physician has been provided with an agent which, when administered to asthmatic patients prior to inhalation of specific antigens, inhibits the release of mediators, e.g. histamine and SRS-A (slow-reacting-substance of anaphylaxis), believed to be responsible for the asthmatic response. While making possible a prophylactic treatment for bronchial asthma without cardiovascular side effects and thus representing a significant advance, disodium cromoglycate suffers from a major disadvantage in that it is not orally absorbed and must be administered by inhalation.
With respect to the compounds of the present invention, no examples of 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-N-(1H-tetrazol-5-yl)carboxamides have been found in the literature. Numerous examples of the pyrido[1,2-a]pyrimidine ring system, however, are known, including many oxo derivatives.
U.S. Pat. No. 3,585,198 reviews some of the literature of the pyrido[1,2-a]pyrimidines and discloses compounds of the general formula ##STR1## where R, R.sup.1, R.sup.2 and R.sup.3 may be hydrogen, alkyl, alkoxy, halogen, nitro or amino, R.sup.4 is hydrogen, alkyl, aralkyl, aryl, .dbd.O, alkoxy, halogen or hydroxy, R.sup.5 is hydrogen, halogen, a --CH.sub.2 --OH group, a carboxylic acid or carboxylic acid derivative group, R.sup.6 is hydrogen, alkyl, aralkyl, aryl, .dbd.O, alkoxy, halogen or hydroxy and R.sup.7 is hydrogen, alkyl, aryl, or alkyl. The disclosed compounds are said to exhibit analgesic, antipyretic and narcosis potentiating effects.
U.S. Patent 3,929,787 discloses 2-aryl-9-alkyl-4H-pyrido[1,2-a]pyrimidin-4-one compounds of the formula ##STR2## where R.sup.1 is phenyl or substituted phenyl, R.sup.2 is hydrogen or alkyl and R.sup.3 is alkyl. These compounds are reported to be intermediates in preparing the corresponding 6,7,8,9-tetrahydro derivatives which possess central nervous system depressant activity.
U.S. Pat. No. 3,072,485 discloses inter alia compounds of the formula ##STR3## where R is hydrogen, bromo, chloro, iodo or methyl. The compounds are used as photographic sensitizers.
Compounds of the formula ##STR4## where R is hydrogen, 9-methyl or 8-methyl are disclosed by Okamoto, et al. in Chem. Pharm. Bull. (Tokyo), 22, 243 (1974). No pharmacological utility for the compounds is indicated.
U.S. Pat. No. 3,960,847 discloses inter alia 9-substituted pyrido[1,2-a]pyrimidines of the formula ##STR5## where R.sup.1 is hydrogen or C.sub.1 -C.sub.4 alkyl, R.sup.2 and R.sup.3 are hydrogen, C.sub.1 -C.sub.4 alkyl, CF.sub.3, F, Cl or Br and R.sup.4 is inter alia an alkyl radical substituted by a phenyl or substituted phenyl radical, such as benzyl, substituted benzyl, phenethyl or substituted phenethyl. The compounds are said to have both central nervous system and hypotensive activities.
J. K. Landquist has described in J. Chem. Soc. (C), 2735 (1971) the preparation of the carboxamide compound of the formula ##STR6## by treatment of the corresponding ethyl ester with ammonium hydroxide in ethanol. No pharmacological utility is given for the disclosed carboxamide.
Other references to the chemistry of pyrido[1,2-a]-pyrimidinones include J. Amer. Chem. Soc., 74, 5491 (1952), J. Org. Chem., 33, 3015 (1968), Arzneim.-Forsch., 22, 815 (1972) and Tetrahedron Lett., (12), 1019 (1975).